Alzheimer Disease
Conditions
Brief summary
This protocol is designed to serve as a pre-screening study for subjects who are potentially eligible for Alzheimer's Disease (AD) therapeutic trials that require tau imaging for inclusion by means of a flortaucipir F18 Positron Emission Tomography (PET) scan.
Interventions
DRUGFlortaucipir F18
370 megabecquerel (MBq) IV single-dose
PROCEDUREBrain PET Scan
positron emission tomography (PET) scan of the brain
Sponsors
Avid Radiopharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Men or women between the ages of 60 and 85 years of age at the time of consent * Patients with gradual and progressive change in memory function for a period equal to or greater than six months * Patients who have a Mini Mental State Examination (MMSE) score in the 20-27 range * Patients who are willing to undergo a PET scan using flortaucipir F 18 * Patients who give informed consent or have a legally authorized representative (LAR) to consent for enrollment
Exclusion criteria
* Patients who lack adequate premorbid literacy, vision, or hearing to complete the required psychometric testing in the investigator's opinion * Females of childbearing potential who are not surgically sterile, not refraining from sexual activity, or not using reliable contraception methods. Females of childbearing potential must not be pregnant (negative serum β-Human Chorionic Gonadotropin \[HCG\] at screening and negative urine β-HCG prior to flortaucipir F 18 injection) or breastfeeding at screening. Females should agree to avoid becoming pregnant by refraining from sexual activity or using reliable contraceptive methods for 24 hours following flortaucipir F 18 injection administration. * Have significant neurological disease affecting the Central Nervous System (CNS) (other than AD) that may affect cognition or ability to complete the study, including but not limited to, other types of dementia, serious brain infections, Parkinson's disease, multiple concussions, or epilepsy or recurrent seizures (except febrile childhood seizures). * Patients with any current primary psychiatric diagnosis other than AD if, in the opinion of the investigator, the disorder/symptom is likely to confound interpretation of drug effect, affect cognitive assessment, or affect the patient's ability to complete the study (patients with history of schizophrenia or other chronic psychosis are excluded). * Intend to use drugs known to significantly prolong the QT interval within 14 days or 5 half-lives (whichever is longer) of a scheduled screening/baseline flortaucipir F 18 PET scan, or have medical history of risk factors for Torsades du Pointes. * Have an average electrocardiography (ECG) corrected QT (QTcF) interval measurement \> 450 msec (men) or \> 470 msec (women) at screening (as determined at the investigational site). * Have ocular pathology that significantly limits ability to reliably evaluate vision or the retina. * Have a history of alcohol or drug disorder (except tobacco use disorder) within 2 years before the screening visit * Have a current serious or unstable illness including retinal, cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses in this study; or has a life expectancy of less than 24 months. * Has a history of cancer within the last five years, with the exception of non-metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical cancer, non-progressive prostate cancer, or other cancers with low risk of recurrence or spread * Patients with a past history (suspected or confirmed) of Hepatitis B or Hepatitis C * History of vitiligo and/or current evidence of post-inflammatory hypopigmentation * Have had prior treatment with a passive anti-amyloid immunotherapy less than five half-lives prior to randomization. * Have previously participated in any other study investigating active immunization against amyloid beta (Aβ) * Patients that are currently enrolled in any other interventional clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study * Contraindication to PET * Has hypersensitivity to flortaucipir F 18 or any of its excipients * Present or planned exposure to ionizing radiation that, in combination with the planned administration of study PET ligands, would result in a cumulative exposure that exceeds local recommended exposure limits * Has previous magnetic resonance imaging (MRI) evidence of significant abnormality that would suggest another potential etiology for progressive dementia or a clinically significant finding that may impact patient's potential to safely participate in study * Have contraindications for MRI, including claustrophobia or the presence of contraindicated metal (ferromagnetic) implants/cardiac pacemaker * Have poor venous access * Are investigator site personnel directly affiliated with this study and/or immediate families; immediate family is defined as a spouse, parent, child, or sibling (biological or legally adopted) * Are Lilly employees or are employees of third-party organizations (TPOs) involved in a study that requires exclusion of their employees * Are otherwise unsuitable for a study of this type in the opinion of the investigator * Have received treatment with a stable dose of an acetylcholinesterase inhibitor (AChEI) and/or memantine for less than two months before randomization (if a patient has recently stopped an AChEI and/or memantine, he/she must have discontinued treatment at least two months before randomization). * Current use of strong inducers of CYP3A * Are currently on medication(s) known to significantly prolong the QT interval * Have allergies to either monoclonal antibodies, diphenhydramine, epinephrine, or methylprednisolone * Have known allergies to LY3002813, related compounds, or any components of the formulation; or history of significant atopy * Have known allergies to LY3202626, related compounds, or any components of the formulation * Changes in concomitant medications that could potentially affect cognition and their dosing should be stable for at least one month before screening, and between screening and randomization (does not apply to medications discontinued due to exclusions or with limited duration of use, such as antibiotics)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Flortaucipir Qualitative Results (Visual Reads) | baseline scan | Flortaucipir PET scans were rated visually by an expert reader as follows: Not consistent with an AD pattern (τAD-), Moderate AD pattern (τAD+), or Advanced AD pattern and likely to progress (τAD++). Eligibility for AACG study was determined from the flortaucipir PET scan quantitation (SUVr; see below) according to protocol-specified criteria that excluded subjects with tau PET signal that was above or below study criteria. |
| Flortaucipir Quantitative Results (SUVr) | baseline scan | Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain. Visual read categories as described for previous measure. Eligibility for AACG study was determined from the flortaucipir PET scan quantitation (SUVr; see below) according to protocol-specified criteria that excluded subjects with tau PET signal that was above or below study criteria. |
Countries
Canada, United States
Participant flow
Recruitment details
Enrollment occurred between Nov 2017 and Aug 2018. Recruited subjects with clinically diagnosed early AD who were interested in participating in AD therapeutic clinical trial AACG (Eli Lilly and Company; TRAILBLAZER-ALZ; NCT03367403)
Participants by arm
| Arm | Count |
|---|---|
| Early Symptomatic AD Subjects Early Symptomatic AD subjects in the flortaucipir PET scan arm | 155 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Other | 1 |
| Overall Study | Technical difficulties | 2 |
Baseline characteristics
| Characteristic | Early Symptomatic AD Subjects |
|---|---|
| Age, Continuous | 74.7 years STANDARD_DEVIATION 6.19 |
| MMSE | 24.5 units on a scale STANDARD_DEVIATION 2.18 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 137 Participants |
| Sex: Female, Male Female | 76 Participants |
| Sex: Female, Male Male | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 155 |
| other Total, other adverse events | 2 / 155 |
| serious Total, serious adverse events | 0 / 155 |
Outcome results
Primary
Flortaucipir Qualitative Results (Visual Reads)
Flortaucipir PET scans were rated visually by an expert reader as follows: Not consistent with an AD pattern (τAD-), Moderate AD pattern (τAD+), or Advanced AD pattern and likely to progress (τAD++). Eligibility for AACG study was determined from the flortaucipir PET scan quantitation (SUVr; see below) according to protocol-specified criteria that excluded subjects with tau PET signal that was above or below study criteria.
Time frame: baseline scan
Population: Includes all subjects who completed the study with valid flortaucipir PET scan (n=152)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Early Symptomatic AD, Eligible for AACG Study | Flortaucipir Qualitative Results (Visual Reads) | τAD-, pattern not consistent with AD | 0 Participants |
| Early Symptomatic AD, Eligible for AACG Study | Flortaucipir Qualitative Results (Visual Reads) | τAD+, moderate AD pattern | 2 Participants |
| Early Symptomatic AD, Eligible for AACG Study | Flortaucipir Qualitative Results (Visual Reads) | τAD++, advanced AD pattern | 56 Participants |
| Early Symptomatic AD, Ineligible for AACG Study | Flortaucipir Qualitative Results (Visual Reads) | τAD+, moderate AD pattern | 8 Participants |
| Early Symptomatic AD, Ineligible for AACG Study | Flortaucipir Qualitative Results (Visual Reads) | τAD++, advanced AD pattern | 22 Participants |
| Early Symptomatic AD, Ineligible for AACG Study | Flortaucipir Qualitative Results (Visual Reads) | τAD-, pattern not consistent with AD | 64 Participants |
| Early Symptomatic AD (Total) | Flortaucipir Qualitative Results (Visual Reads) | τAD++, advanced AD pattern | 78 Participants |
| Early Symptomatic AD (Total) | Flortaucipir Qualitative Results (Visual Reads) | τAD-, pattern not consistent with AD | 64 Participants |
| Early Symptomatic AD (Total) | Flortaucipir Qualitative Results (Visual Reads) | τAD+, moderate AD pattern | 10 Participants |
Primary
Flortaucipir Quantitative Results (SUVr)
Flortaucipir standardized uptake value ratio (SUVr). A value of 1 signifies no flortaucipir activity above background, values greater than 1 signify increasing flortaucipir activity in the brain. Visual read categories as described for previous measure. Eligibility for AACG study was determined from the flortaucipir PET scan quantitation (SUVr; see below) according to protocol-specified criteria that excluded subjects with tau PET signal that was above or below study criteria.
Time frame: baseline scan
Population: SUVr was not collected for patients with a τAD- result
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Early Symptomatic AD, Eligible for AACG Study | Flortaucipir Quantitative Results (SUVr) | SUVr all | 1.21207 standardized uptake value ratio (SUVr) | Standard Deviation 0.119729 |
| Early Symptomatic AD, Eligible for AACG Study | Flortaucipir Quantitative Results (SUVr) | SUVr τAD++ subjects | 1.21518 standardized uptake value ratio (SUVr) | Standard Deviation 0.120696 |
| Early Symptomatic AD, Eligible for AACG Study | Flortaucipir Quantitative Results (SUVr) | SUVr τAD+ subjects | 1.12490 standardized uptake value ratio (SUVr) | Standard Deviation 0.012021 |
| Early Symptomatic AD, Ineligible for AACG Study | Flortaucipir Quantitative Results (SUVr) | SUVr τAD+ subjects | 1.00991 standardized uptake value ratio (SUVr) | Standard Deviation 0.023239 |
| Early Symptomatic AD, Ineligible for AACG Study | Flortaucipir Quantitative Results (SUVr) | SUVr τAD++ subjects | 1.65880 standardized uptake value ratio (SUVr) | Standard Deviation 0.143067 |
| Early Symptomatic AD, Ineligible for AACG Study | Flortaucipir Quantitative Results (SUVr) | SUVr all | 1.48576 standardized uptake value ratio (SUVr) | Standard Deviation 0.316435 |
| Early Symptomatic AD (Total) | Flortaucipir Quantitative Results (SUVr) | SUVr all | 1.30537 standardized uptake value ratio (SUVr) | Standard Deviation 0.244527 |
| Early Symptomatic AD (Total) | Flortaucipir Quantitative Results (SUVr) | SUVr τAD++ subjects | 1.34031 standardized uptake value ratio (SUVr) | Standard Deviation 0.237395 |
| Early Symptomatic AD (Total) | Flortaucipir Quantitative Results (SUVr) | SUVr τAD+ subjects | 1.03291 standardized uptake value ratio (SUVr) | Standard Deviation 0.052789 |